3-Substituted cephalosporins, and their use as medicaments

ABSTRACT

The invention relates to new 3-substituted cephalosporins, a process for their preparation and their use as medicaments, in particular as medicaments having antibacterial activitity.

The invention relates to new 3-substituted cephalosporins, a process fortheir preparation and their use as medicaments, in particular asmedicaments having anti-bacterial activity.

EP 192,210 A2 discloses 7-substitutedcyclopropyloximinoacetamido-cephem-carboxylic acids having antibacterialactivity.

In the publication JP 56 104,812, cephalosporins of which the 7-positioncan be substituted by an oximino function and the 3-position can also besubstituted by a phenyl ring are encompassed by the width of the claims,no actual representative substance being mentioned.

The invention relates to compounds of the general formula (I) ##STR1##in which

X represents a nitrogen atom or the --CH group,

Y represents a group of the formula N--OR₃ or CHR₄ in which

R₃ denotes hydrogen straight-chain or branched alkenyl, alkinyl or alkylin each case having up to 8 carbon atoms, where the latter canoptionally be substituted by halogen or by protected or unprotectedcarboxyl or amino,

R₄ denotes hydrogen, aryl having 6 to 10 carbon atoms, protected orunprotected carboxyl, halogen or straight-chain or branchedalkoxycarbonyl, alkoxy, alkenyl or alkyl in each case having up to 8carbon atoms, where the latter can be substituted by halogen, hydroxyl,nitro, cyano, carboxyl or by straight-chain or branched alkoxy oralkoxycarbonyl in each case having up to 6 carbon atoms,

R₁ represents thienyl, furyl or phenyl which are optionallymonosubstituted to trisubstituted by identical or different halogen,trifhoromethyl, trifhoromethoxy or hydroxyl substituents or by a groupof the formula --NR₅ R₆ in which

R₅ and R₆ are identical or different and denote hydrogen, straight-chainor branched alkyl having up to 8 carbon atoms or phenyl,

or are substituted by straight-chain or branched alkoxy or alkyl in eachcase having up to 8 carbon atoms, where the latter can be substituted byhydroxyl, halogen or by straight-chain or branched alkoxy having up to 6carbon atoms,

R₂ represents hydrogen, or represents a carboxyl protecting group orrepresents an ester radical which can be cleaved in vivo,

and their pharmaceutically tolerable salts.

Because of the presence of double bonds (═Y), the compounds of thegeneral formula (I) according to the invention can occur as pure syn- oranti-isomers or as mixtures of isomers. The syn-isomers of the compoundsof the general formula (I) according to the invention are preferred.

Both the isomer mixtures and the syn- and anti-form of the compoundsaccording to the invention can be employed for the treatment ofbacterial infectious diseases.

The compounds of the general formula (I) can be present as free acids,esters, as internal salts or as non-toxic pharmaceutically tolerablesalts of the acidic carboxyl groups such as sodium, potassium,magnesium, calcium, aluminium or ammonium salts, with amines such as di-and tri-lower alkylamines, procaine, dibenzylamine,N,N'-di-benzylethylenediamine, N-benzyl-β-phenyl-ethylamine, N-methyl-and N-ethylmorpholine, 1-ephenamine, dihydroabietylamine,N,N'-bis-dehydroabietylethylenediamine, N-lower alkylpiperidine andother amines which can be used for the formation of salts of penicillinsand cephalosporins.

Examples of non-toxic, pharmaceutically tolerable salts of the basicamino groups with inorganic or organic acid radicals which canpreferably be mentioned are chloride, bromide, iodide, sulphate,hydrogen sulphate, phosphate, carbonate, hydrogen carbonate, orsulphonates such as methylsulphonate, ethanesulphonate,toluenesulphonate, benzenesulphonate, naphthalenedisulphonate, orcarboxylates such as acetate, formate, oxalate, tartrate, citrate,maleate, fumarate, benzoate, succinate or lactate.

Amino or oxime protecting group in the context of the abovementioneddefinition in general represents a protecting group customary inβ-lactam chemistry from the series comprising: tert-butoxycarbonyl,benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,phenylacetyl, allyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,allyloxymethyl, bis-(4-methoxyphenyl)-methyl,2-(methylthiomethoxy)ethoxycarbonyl, trimethyl-, triethyl-,triphenylsilyl, trityl, tert-butyl-dimethylsilyl,tert-butyldiphenylsilyl, [2-(trimethylsilyl)ethoxy]methyl,1-methyl-2-benzoyl-vinyl, 1-methyl-2-methoxyvinyl,1-methyl-2-acetyl-vinyl, 1-methyl-2(methoxybenzoyl)-vinyl,1-methyl-2-(2,6-dimethoxybenzoyl)vinyl and1-methyl-2-ethoxycarbonyl-vinyl.

Carboxyl protecting group in the context of the above-mentioneddefinition represents the carboxyl protecting group customary inβ-lactam chemistry. Easily cleavable groups can preferably be mentioned,such as, for example: tert-butyl, 2,2,2-trichloroethyl, diphenylmethyl,triphenylmethyl, acetoxymethyl, allyl, benzyl, 4-methoxyphenyl,4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl,trimethylsilylethyl, trimethylsilyl, tert-butyl-dimethylsilyl, acetonyl,1-phenoxyethyl or 2-methyl-2-propenyl.

If R₂ represents an ester radical which can be easily cleaved in vivo,pharmaceutically tolerable ester radicals which are easily hydrolysed invivo to give free carboxyl groups (R₂ ═H) are meant by this.

Such ester radicals are well-known in the β-lactam field. In most cases,they improve the absorption properties of the β-lactam compounds. The R²radical should additionally be of a type such that it impartspharmaceutically acceptable properties to a compound of the formula (I)and on cleavage in vivo releases pharmaceutically acceptable fragments.

Examples of such groups are found in German Offenlegungsschrift2,517,316. Preferred ester groups which can be cleaved in vivo are thoseof the following formulae: ##STR2## in which

R₇ and R₈ are identical or different and denote hydrogen, phenyl orstraight-chain or branched alkyl having up to 4 carbon atoms,

R₉, R_(9') and R_(10') are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms,

R¹¹ denotes straight-chain or branched alkyl having up to 6 carbonatoms,

R¹² denotes straight-chain or branched alkyl having up to 6 carbon atomsor cyclohexyl.

Preferred compounds of the general formula (I) are those in which

X represents a nitrogen atom or the --CH group,

Y represents a group of the formula N--OR₃ or CHR₄, in which

R³ denotes hydrogen or straight-chain or branched alkyl having up to 6carbon atoms, which is optionally substituted by fluorine, chlorine,bromine or protected or unprotected carboxyl or amino,

R⁴ denotes hydrogen, phenyl, carboxyl, fluorine, chlorine, bromine orstraight-chain or branched alkoxy, alkoxycarbonyl or alkyl in each casehaving up to 6 carbon atoms, where the latter can be substituted byfluorine, chlorine, bromine, hydroxyl, carboxyl or by straight-chain orbranched alkoxy or alkoxycarbonyl in each case having up to 4 carbonatoms,

R₁ represents thienyl, furyl or phenyl, which are optionallymonosubstituted or disubstituted by identical or different fluorine,chlorine Or bromine substituents, or by a group of the formula --NR⁵ R⁶,in which

R₅ and R₆ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 6 carbon atoms,

or are substituted by straight-chain or branched alkoxy or alkyl in eachcase having up to 6 carbon atoms, where the latter can be substituted byhydroxyl, fluorine, chlorine or by straight-chain or branched alkoxyhaving up to 4 carbon atoms,

R₂ represents hydrogen, or represents methyl, ethyl, tert-butyl,2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl,triphenylmethyl, acetoxymethyl, allyl, benzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 1-phenoxyethyl, 2-methyl-2-propenyl, 4-nitrobenzyl,2-nitrobenzyl, trimethylsilylethyl or tert-butyl-dimethylsilylethyl, orrepresents a radical of the formula ##STR3## and their pharmaceuticallytolerable salts.

Particularly preferred compounds of the general formula (I) are those inwhich

X represents a nitrogen atom or the --CH group,

Y represents a group of the formula N--OR₃ or --CHR₄, in which

R₃ denotes hydrogen or straight-chain or branched alkyl having up to 4carbon atoms, which is optionally substituted by fluorine, chlorine orby protected or unprotected carboxyl or amino,

R₄ denotes hydrogen or straight-chain or branched alkoxy or alkyl ineach case having up to 4 carbon atoms, where the latter can besubstituted by hydroxyl, carboxyl, methoxy, ethoxy or propoxy,

R₁ represents thienyl, furyl or phenyl, which are optionallymonosubstituted or disubstituted by identical or different fluorine,chlorine, bromine or amino substituents or by straight-chain or branchedalkoxy, alkoxycarbonyl or alkyl in each case having up to 4 carbonatoms, where the latter can be substituted by hydroxyl, fluorine,chlorine, methoxy or ethoxy,

R₂ represents hydrogen, or represents a radical of the formula ##STR4##and their pharmaceutically tolerable salts.

The sodium salts are very particularly preferred.

A process for the preparation of the compounds of the general formula(I) according to the invention has furthermore been found, characterisedin that compounds of the general formula (II) 0 ##STR5## in which

R₁ has the abovementioned meaning and

R₂ ' represents one of the abovementioned carboxyl protecting groups, inparticular p-methoxybenzyl, are reacted, if appropriate also withactivation of the amino function, with compounds of the general formula(III) ##STR6## in which

Y₁ represents one of the abovementioned groups N--OR_(3') or CHR_(4'),in which

R_(3') has the abovementioned meaning of R³ or represents one of theabovementioned oxime protecting groups, in particular the tritylradical,

R_(4') has the abovementioned meaning of R₄ or represents protectedcarboxyl and

R₁₃ also represents one of the abovementioned amino protecting groups,preferably BOC or the trityl radical,

in inert solvents, if appropriate with activation of the carboxyl groupin the presence of an auxiliary, initially to give the compounds of thegeneral formula (IV) ##STR7## in which

R₁, R₂, R₁₃ and Y' have the abovementioned meaning, and the protectinggroups R₂, R^(3'), R_(4') (Y') and R₁₃ are then removed by a customarymethod, if appropriate in 2 steps, and the desired salts are prepared orthe free acids are prepared from the salts.

The process according to the invention can be illustrated by way ofexample by the following reaction scheme: ##STR8##

Suitable solvents are all solvents which do not change under thereaction conditions. These preferably include ethers such as, forexample, diethyl ether, dioxane or tetrahydrofuran, orchlorohydrocarbons such as methylene chloride, chloroform ortetrachloromethane, or amides such as dimethylformamide orhexamethylphosphoric triamide, or acetonitrile or acetone. It is alsopossible to employ mixtures of the solvents mentioned. Methylenechloride is preferred.

The condensation is in general carried out in a temperature range from0° C. to +60° C., preferably at room temperature and at normal pressure.

The activation of the carboxyl group in the compounds of the generalformula (III) is in general carried out by conversion into a mixedanhydride using esters of chloroformic acid or sulphonic acidderivatives, such as, for example, ethyl chloroformate, isobutylchloroformate or methanesulphonyl chloride, by conversion into thecorresponding acid halide, or by conversion into an activated ester, forexample using N-hydroxybenzotriazole or dicyclohexylcarbodiimide.Reaction with ethyl chloroformate or methanesulphonyl chloride ispreferred.

The activation of the amino function of the compounds of the generalformula (II) is carried out by a customary method, for example byconversion into the corresponding silyl derivatives by reaction withbis(trimethylsilyl)-acetamide, N-trimethylsilylacetamide orbis(trimethylsilyl)urea.

Auxiliaries employed are preferably condensing agents which can also bebases, in particular if, for example, the carboxyl group is present inactivated form as the anhydride. Those preferably employed here are thecustomary condensing agents such as carbodiimides, for exampleN,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl- orN,N'-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride, orcarbonyl compounds such as carbonyldiimidazole, or 1,2-oxazoliumcompounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbenzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate, oras bases alkali metal carbonates, for example sodium carbonate orpotassium carbonate or sodium hydrogen carbonate or potassium hydrogencarbonate, or organic bases such as trialkylamines, for exampletriethylamine, N-ethylmorpholine or N-methylpiperidine.

The removal of the protecting groups is carried out by a customarymethod, in the case of the oximes if desired successively, either usingorganic acids, such as, for example, formic acid, if appropriate in thepresence of water or in the presence of water and a protonic acid, suchas, for example, hydrochloric acid, preferably using formic acid andwater or formic acid, water and hydrochloric acid.

In the case in which R₃ ≠H, it is moreover possible to remove the aminoprotecting group R₁₃, the carboxyl protecting groups R_(2') and theprotecting groups R³ and R^(4') using trifluoroacetic acid, ifappropriate in one step.

The removal of the protecting groups is in general carried out in atemperature range from 0° C. to +80° C., preferably at room temperature.

The removals can be carried out both at normal pressure and at elevatedor reduced pressure (for example 0.5 to 5 bar), preferably at normalpressure.

The compounds of the general formula (II) are in some cases encompassedby the width of the claims of other publications, such as, for example,in EP 192,210 A2 and can be prepared in analogy to processes known fromthe literature [cf. U.S. Pat. No. 4,855,4 18; Tetrahedron Lett., vol.29, No. 47, 6043-6046, 1988]by reacting, for example, p-methoxybenzyl7-phenacetylamino-3-trifluoromethanesulphonyl-3-cephem-4-carboxylate ofthe formula (V) ##STR9## in which

R_(2') has the abovementioned meaning, with compounds of the generalformula (VI)

    R.sup.1 --Z                                                (VI)

in which

R₁ has the abovementioned meaning and

Z represents an organotin radical defined in the following,

in aprotic polar solvents, in the presence of metal halides, phosphinesand a catalyst, to give compounds of the general formula (VII) ##STR10##in which R₁ and R_(2') have the abovementioned meaning, and in a laststep deblocking the amino function according to a customary method, forexample by the action of the system 1.) PCl₅ /pyridine/methylenechloride and 2.) HN(C₂ H₅)₂ /methanol.

Suitable organotin radicals ( Z ) are, for example, tri-methylstannyl,triethylstannyl or tributylstannyl. Tri-n-butylstannyl is preferred.

Suitable metal halides are zinc, lithium and magnesium halides, such as,for example, ZnCl₂, ZnBr₂, LiC1, LiBr, MgCl₂. or MgBr₂. ZnCl₂ ispreferred.

Suitable catalysts are Pd(O) and (II) complexes, such as, for example,bis (dibenzylidene-acetonyl ) palladium [(Pd/dba)₂ ], Pd₂ dba₃ ×CHCl₃ orPd(OAc)₂ ·Pd₂ dba₃ ×CHCl₃ is preferred.

Suitable aprotic polar solvents are, for example, acetonitrile, dimethylsulphoxide (DMSO), dimethylformamide (DMF), or ethers such as glyme,dioxane or THF, or acetone, hexamethylphosphoramide, orN-methylpyrrolidone or 1-methyl-2-pyrrolidone. N-Methylpyrrolidone ispreferred.

Phosphines which can be employed are, for example, triphenyl phosphine,tri-( 3-fluorophenyl )-phosphine, diphenylmethylphosphine,tributylphosphine, tri-( 2-thienyl )phosphine or tri-( 2-furyl)phosphine. Tri-(2-furyl)phosphine is preferred.

The reaction is carried out in a temperature range from -30° C. to +90°C., preferably at room temperature and normal pressure.

The compound of the general formula (V) is known per se [J. Org. Chem.1989, 54, 4962-4966].

The compounds of the general formula (VI) are known per se and can beprepared and employed according to processes known from the literature[cf. EP 343,277 A1].

The compounds of the general formula (VII) are new with respect to theabovementioned definition of R¹ but can be prepared in analogy to knownprocesses [cf. J. Org. Chem., Vol. 54, No. 20, 1989].

The compounds of the general formula (III) are known per se or can beprepared by a customary method [cf. Tetrahedron, Vol. 34, 2233-2243].

The compounds of the general formula (IV) are new and can be prepared bythe abovementioned process.

The compounds of the general formula (I) according to the invention havea broad antibacterial spectrum against Gram-positive and Gram-negativemicroorganisms and a low toxicity. These properties make possible theiruse as chemotherapeutic active compounds in human and veterinarymedicine.

The compounds according to the invention are active against a very broadspectrum of microorganisms. Gram-negative and Gram-positive bacteria andbacteria-like microorganisms can be controlled with their aid and thediseases caused by these pathogens can be prevented, ameliorated and/orcured.

The compounds according to the invention are particularly active againstbacteria and bacteria-like microorganisms. They are thereforeparticularly well suited in human and veterinary medicine for theprophylaxis and chemotherapy of local and systemic infections which arecaused by such pathogens.

The minimum inhibitory concentrations (MIC) were determined by theserial dilution method on iso-sensitest agar (oxoid). A series of agarplates which contained concentrations of the active compound decreasingin double dilutions in each case were prepared for each test substance.The agar plates were inoculated using a multipoint inoculator (Denley).For the inoculation, overnight cultures of the pathogens were used whichwere previously diluted in such a way that each inoculation pointcontained about 10⁴ colony-forming particles. The inoculated agar plateswere incubated at 37° C. and the bacterial growth was read off afterabout 20 hours. The MIC value (μg/ml) indicates the lowest activecompound concentration at which no bacterial growth could be detectedwith the naked eye.

USE EXAMPLE

MIC values: agar dilution/multipoint

    ______________________________________                                        Microorganisms   XVIII     XVI                                                ______________________________________                                        E. coli T7       2         1                                                  E. coli Neumann  0.5       0.5                                                E. coli 183/58   4         4                                                  E. coli F14      2         2                                                  E. coli C 165    2         2                                                  E. coli 4322     <0.25     0.5                                                Klebs. 57 USA    <0.25     0.5                                                Klebs. 63        2         2                                                  Klebs. 1852      2         2                                                  Klebs. 6097      2         2                                                  Serratia 16001   4         4                                                  Serratia 16002   16        16                                                 Provid. 12012    <0.25     <0.25                                              Prot. morg. 932  32        128                                                Prot. vulg. 9032 0.5       4                                                  Prot. vulg. 1017 <0.25     0.5                                                Prot. vulg. N6   16        4                                                  Prot. rettg. 10007                                                                             2         2                                                  Prot. mir. 1235  1         1                                                  Staph. aur. 1756 64        128                                                Staph. aur. 133  1         1                                                  Staph. aur. 25455                                                                              1         1                                                  Staph. aur. 25470                                                                              1         2                                                  Strepto. faec. 27101                                                                           128       >128                                               Strepto. faec. 113                                                                             2         2                                                  Enterococ. 9790  128       >128                                               Enterococ. 27158 2         2                                                  Psdm. aerug. F41 >128      >128                                               Psdm. aerug. Walter                                                                            >128      > 128                                              Psdm. aerug. 7035                                                                              >128      >128                                               Psdm. aerug. 7451                                                                              >128      >128                                               Enterob. cl. 5605                                                                              >128      >128                                               Enterob. cl. 5744                                                                              4         4                                                  Acinetop. 14061  32        32                                                 ______________________________________                                    

The present invention includes pharmaceutical preparations which containone or more compounds according to the invention in addition tonon-toxic, inert pharmaceutically suitable excipients or which consistof one or more active compounds according to the invention, andprocesses for the production of these preparations.

The active compound(s) can optionally also be present inmicroencapsulated form in one or more of the abovementioned excipients.

The therapeutically active compounds should preferably be present in theabovementioned pharmaceutical preparations in a concentration of about0.1 to 99.5, preferably of about 0.5 to 95% by weight of the totalmixture.

The abovementioned pharmaceutical preparations can also contain otherpharmaceutical active compounds in addition to the compounds accordingto the invention.

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active compound(s) according to the inventionin total amounts of about 0.5 to about 500, preferably 5 to 100, mg/kgof body weight every 24 hours, if appropriate in the form of severalindividual doses, to achieve the desired results. An individual dosepreferably contains the active compound(s) according to the invention inamounts of about 1 to about 80, in particular 3 to 30, mg/kg of bodyweight.

The new compounds can be combined in the customary concentrations andpreparations together with the feed and/or lactamase inhibitors, forexample with penicillins which are particularly resistant topenicillinase and clavulanic acid. Such a combination would be, forexample, that with oxacillin or dicloxacillin.

The compounds according to the invention can also be combined withaminoglycoside antibiotics, such as, for example, gentamicin, sisomicin,kanamicin, amicacin or tobramicin for the purpose of extending thespectrum of action and in order to achieve an increase in action.

¹ H-NMR data exist for all compounds.

STARTING COMPOUNDS EXAMPLE I

(2-Methoxymethyl-3-thienyl )-tri-n-butyl-stannane ##STR11##

19.2 g (150 mmol) of 2-methoxymethyl-thiophene are added dropwise at-78° C. to a solution of 150 mmol of n-butyllithium in 500 ml of THF.The mixture is allowed to warm to 0° C. and is cooled again to -78° C.after 5 min, and 43.4 ml (160mmol) of tributyltin chloride are added.The cooling bath is removed and the mixture is stirred overnight at roomtemperature. 500 ml of saturated ammonium chloride solution are addedfor working up. The mixture is extracted with ether, the combinedorganic phases are dried and the solvent is removed. Afterchromatography on silica gel using petroleum ether, 17.7 g (28% oftheory) of the title compound are obtained.

EXAMPLE 2

4-Bromo- 2-methoxymethyl-thiophene ##STR12##

A mixture of 48.2 g (0.25 mol) of 4-bromo-2-hydroxymethyl-thiophene and15.7 ml (0.25 mol) of methyl iodide is added dropwise to a suspension of7.5 g (0.25 mol) of 80% strength sodium hydride. The mixture is stirredovernight, the solvent is stripped off, the residue is partitionedbetween methylene chloride and water (1.0 1 each), and the organic phaseis separated off and dried using sodium sulphate. After the removal ofthe solvent, the residue is chromatographed on silica gel usingtoluene/petroleum ether (1:1).

Yield: 48.2 g (93% of theory)

EXAMPLE 3

(4-Bromo-2-methoxymethyl- 3-thienyl ) -tri-n-butyl-stannane ##STR13##

31.1 g (150 mmol ) of the compound from Example 2 are added dropwise at-78° C. under argon to a solution of 150 mmol of n-butyllithium. Themixture is allowed to warm to -40° C. and is cooled again to -78° C.after 20 min, and 43.4 ml (160 mmol) of tributyltin chloride are added.The solution is stirred overnight at room temperature and saturatedammonium chloride solution and methylene chloride are added. The organicphase is separated off and dried using sodium sulphate. After distillingoff the solvent, the residue is chromatographed on silica gel usingpetroleum ether.

Yield: 19.5 g (26% of theory)

EXAMPLE 4

p-Methoxybenzyl 7β-phenacetylamino- 3- (2-thienyl ) -3-cephem-4-carboxylate ##STR14##

4.68 g (8.0 mmol) of p-methoxybenzyl7-phenacetylamino-3-trifluoromethanesulphonyl-3-cephem-4-carboxylate areallowed to react under argon overnight at room temperature with 2.98 g(8.0 mmol) of 2-thienyl-tri-n-butylstannane, 1.90 g (13.9 mmol) of zincchloride, 0.34 g (1.46 mmol) of tri-2-furyl-phosphine and 0.35 g (0.34mmol) of tris-(dibenzylideneacetone)-dipalladiumchloroform in 130 ml ofanhydrous N-methylpyrrolidone. The mixture is then poured into 400 ml ofwater and the precipitate deposited is filtered off with suction. Theresidue, dissolved in 400 ml of methylene chloride, is dried usingsodium sulphate and chromatographed on silica gel using toluene/ethylacetate (5:1) after the removal of the solvent.

Yield: 2.52 g (61% of theory)

The following compounds are prepared in analogy to the procedure ofExample 4:

    ______________________________________                                         ##STR15##                                                                    Example No.: R.sub.1                                                          ______________________________________                                         5                                                                                          ##STR16##                                                        6                                                                                          ##STR17##                                                        7                                                                                          ##STR18##                                                        8                                                                                          ##STR19##                                                        9                                                                                          ##STR20##                                                       10                                                                                          ##STR21##                                                       11                                                                                          ##STR22##                                                       12                                                                                          ##STR23##                                                       13                                                                                          ##STR24##                                                       14                                                                                          ##STR25##                                                       15                                                                                          ##STR26##                                                       ______________________________________                                    

EXAMPLE 16

p-Methoxybenzyl 7β-phenacetylamino-3-(3-thienyl )-3-cephem-4-carboxylate##STR27##

In analogy to the procedure of Example 4, 2.69 g (65% of theory) of thetitle compound are prepared from 2.98 g (8.0 mmol ) of3-thienyl-tri-n-butyl-stannane.

EXAMPLE 17

p-Methoxybenzyl3-(2-methoxymethyl-3-thienyl)-7β-phenacetyl-amino-3-cephem-4-carboxylate##STR28##

In analogy to the procedure of Example 4, 1.9 g (42% of theory) of thetitle compound are prepared from 3.3 g (8.0 mmol) of the compound fromExample 1.

EXAMPLE 18

p-Methoxybenzyl 3-(4-bromo-2-methoxymethyl-3-thienyl)-7β-phenacetyl-amino-3-cephem-4-carboxylate ##STR29##

In analogy to the procedure of Example 4, 1.20 g (27% of theory) of thetitle compound are prepared from 3.34 g (8.0 mmol) of the compound fromExample 3.

EXAMPLE 19

p-Methoxybenzyl 7β-amino-3-(2-thienyl)-3-cephem-4-carboxylate ##STR30##

2.0 g (9.7 mmol) of phosphorus pentachloride are added at -20° C. to asolution of 2.5 g (4.8 mmol) of the compound from Example 4 and 1.0 ml(12.4 mmol) of pyridine in 55 ml of anhydrous methylene chloride. Themixture is stirred at -20° C. for 5 min, at 0° C. for 10 min and at 15°C. for 1 h, and is then cooled to -78° C. 42 ml of methanol cooled to-78° C. are rapidly added. The solution is stirred at -78° C. for 5 min,at 0° C. for 10 min and at 15° C. for 25 min. After cooling to -15° C.,0.56 ml (5.4 mmol) of diethylamine is added and the mixture is kept atthis temperature for 10 min. It is poured into 150 ml of saturatedsodium hydrogen carbonate solution for working up and the mixture isextracted with methylene chloride. The combined organic phases arewashed with sodium hydrogen carbonate solution and water, dried withsodium sulphate and concentrated. The residue is chromatographed onsilica gel using toluene/ethyl acetate.

Yield: 1.6 g (86% of theory)

The following compounds were prepared in analogy to the procedure ofExample 19:

    ______________________________________                                         ##STR31##                                                                    Example No.: R.sub.1                                                          ______________________________________                                        20                                                                                          ##STR32##                                                       21                                                                                          ##STR33##                                                       22                                                                                          ##STR34##                                                       23                                                                                          ##STR35##                                                       24                                                                                          ##STR36##                                                       25                                                                                          ##STR37##                                                       26                                                                                          ##STR38##                                                       27                                                                                          ##STR39##                                                       28                                                                                          ##STR40##                                                       29                                                                                          ##STR41##                                                       30                                                                                          ##STR42##                                                       ______________________________________                                    

EXAMPLE 31

p-Methoxybenzyl 7β-amino-3-(3-thienyl)-3-cephem-4-carboxylate ##STR43##

In analogy to the procedure of Example 19, 1.65 g (80% of theory) of thetitle compound are prepared from 2.65 g (5.1 mmol) of the compound fromExample 16.

EXAMPLE 32

p-Methoxybenzyl7β-amino-3-(2-methoxymethyl-3-thienyl)-3-cephem-4-carboxylate ##STR44##

In analogy to the procedure of Example 19, 1.1 g (73% of theory) of thetitle compound are obtained from 1.9 g (3.4 mmol ) of the compound fromExample 17.

EXAMPLE 33

p-Methoxybenzyl7β-amino-3-(4-bromo-2-methoxymethyl-3-thienyl)-3-cephem-4-carboxylate##STR45##

In analogy to the procedure of Example 19, 0.89 g (70% of theory) of thetitle compound is obtained from 1.55 g (2.4 mmol) of the compound fromExample 18.

EXAMPLE 34

p-Methoxybenzyl7β-[2-(2-t-butyloxycarbonylamino-4-thiazolyl)-2-syn-methoxyimino-acetylamino]-3-(2-thienyl)-3-cephem-4-carboxylate ##STR46##

A solution of 0.50 g (1.2 mmol) of the compound from Example 19, 1.14 g(3.8 mmol) of2-(2-t-butyloxycarbonyl-amino-4-thiazolyl)-syn-2-methoxyiminoacetic acidand 0.85 g (4.1mmol) of dicyclohexylcarbodiimide in 40 ml ofacetonitrile is stirred overnight. The mixture is concentrated andchromatographed on silica gel using toluene/ethyl acetate (8:1).

Yield: 430 mg (51% of theory)

The following compounds were prepared in analogy to the procedure ofExample 34:

    ______________________________________                                         ##STR47##                                                                    Example No.: R.sub.1                                                          ______________________________________                                        35                                                                                          ##STR48##                                                       36                                                                                          ##STR49##                                                       37                                                                                          ##STR50##                                                       38                                                                                          ##STR51##                                                       39                                                                                          ##STR52##                                                       40                                                                                          ##STR53##                                                       41                                                                                          ##STR54##                                                       42                                                                                          ##STR55##                                                       43                                                                                          ##STR56##                                                       ______________________________________                                    

EXAMPLE 44

p-Methoxybenzyl7β-[2-(2-t-butyloxycarbonylamino-4-thiazolyl)-2-syn-methoxyimino-acetylamino]-3-1-(3-thienyl)-3-cephem-4-carboxylate##STR57##

In analogy to the procedure of Example 34, 0.75 g (44% of theory) of thetitle compound is obtained from 1.00 g (2.5 mmol) of the compound fromExample 31.

EXAMPLE 45

p-Methoxybenzyl 7β-[2- (2-t-butyloxycarbonylamino-4-thiazolyl)-2-syn-methoxyimino-acetylamino]-3-(2-methoxymethyl-3-thienyl)-3-cephem-4-carboxylate##STR58##

In analogy to the procedure of Example 34, 132 mg (37% of theory) of thetitle compound are obtained from 220 mg (0.49 mmol) of the compound fromExample 32.

EXAMPLE 46

p-Methoxybenzyl3-(2-thienyl)-7β-[2-(2-tritylamino-4-thiazolyl)-2-syn-trityloxyimino-acetylamino]-3-cephem-4-carboxylate##STR59##

A solution of 3.36 g (5.0 mmol) of2-(2-tritylamino-4-thiazolyl)-2-syn-trityloxyimino-acetic acid in 50 mlof methylene chloride is stirred at room temperature for 2 h with 1.33 g(6.5 mmol) of dicyclohexylcarbodiimide. 1.00 g (2.5 mmol) of thecompound from Example 19 is added and the mixture is stirred overnightat room temperature. After distilling off the solvent, the residue ischromatographed on silica gel using toluene/ethyl acetate (99:1).

Yield: 1.12 g (45% of theory)

The following compounds were prepared in analogy to the procedure ofExample 46:

    ______________________________________                                         ##STR60##                                                                    Example No.: R.sub.1                                                          ______________________________________                                        47                                                                                          ##STR61##                                                       48                                                                                          ##STR62##                                                       49                                                                                          ##STR63##                                                       50                                                                                          ##STR64##                                                       51                                                                                          ##STR65##                                                       52                                                                                          ##STR66##                                                       53                                                                                          ##STR67##                                                       54                                                                                          ##STR68##                                                       55                                                                                          ##STR69##                                                       56                                                                                          ##STR70##                                                       57                                                                                          ##STR71##                                                       ______________________________________                                    

EXAMPLE 58

p-Methoxybenzyl 3-(3-thienyl)-7β-[2-(2-tritylamino-4-thiazolyl)-2-syn-trityloxyimino-acetylamino]-3-cephem-4-carboxylate##STR72##

In analogy to the procedure of Example 46, 1.53 g (58% of theory) of thetitle compound are prepared from 1.00 g (2.5 mmol) of the compound fromExample 31.

EXAMPLE 59

p-Methoxybenzyl3-(2-methoxymethyl-3-thienyl)-7β-[2-(2-tritylamino-4-thiazolyl)-2-syn-trityloxyimino-acetyl-amino]-3-cephem-4-carboxylate##STR73##

In analogy to the procedure of Example 46, 708 mg (33% of theory) of thetitle compound are prepared from 870 mg (1.95 mmol) of the compound fromExample 32.

EXAMPLE 60

p-Methoxybenzyl3-(4-bromo-2-methoxymethyl-3-thienyl)-7β-[2-(2-trityloxyamino-4-thiazolyl)-2-syn-trityliminoacetylamino]-3-cephem-4-carboxylate##STR74##

In analogy to the procedure of Example 46, 1.18 g (63% of theory) of thetitle compound are obtained from 0.85 g (1.6 mmol) of the compound fromExample 39.

EXAMPLE 61

p-Methoxybenzyl7β-[2-(2-amino-4-thiazolyl)-Z-2-butenoylamino]-3-(3-thienyl)-3-cephem-4-carboxylate ##STR75##

600 mg (1.5 mmol) of the compound from Example 31 and 550 mg (3.0 mmol)of 2-(2-amino-4-thiazolyl )-Z-2-propenecarboxylic acid are stirredovernight at room temperature together with 620 mg (3.0 mmol) ofdicyclohexylcarbodiimide in 40 ml of acetonitrile. The precipitate isfiltered off with suction, the filtrate is concentrated and the residueis chromatographed on silica gel using toluene/ethyl acetate (1:1).

Yield: 590 mg (69% of theory)

PREPARATION EXAMPLES EXAMPLE I

7β-[2-(2-Amino-4-thiazolyl)-2-syn-methoxyimino-acetyl-amino]-3-(2-thienyl)-3-cephem-4-carboxylicacid (tri-fluoroacetate) ##STR76##

420 mg (0.61 mmol) of the compound from Example 34 are treated at roomtemperature for 1 h with a mixture of 1 ml of anisole and 50 ml oftrifluoroacetic acid. The trifluoroacetic acid is then stripped off invacuo and the residue is stirred with ether.

Yield: 324 mg (92% of theory)

The following compounds are prepared in analogy to the procedure ofExample I:

    ______________________________________                                         ##STR77##                                                                    Example No.: R.sub.1                                                          ______________________________________                                        II                                                                                          ##STR78##                                                       III                                                                                         ##STR79##                                                       IV                                                                                          ##STR80##                                                                     ##STR81##                                                       VI                                                                                          ##STR82##                                                       VII                                                                                         ##STR83##                                                       VIII                                                                                        ##STR84##                                                       IX                                                                                          ##STR85##                                                       X                                                                                           ##STR86##                                                       ______________________________________                                    

EXAMPLE XI

7β-2-(2-Amino-4-thiazolyl)-2-syn-methoxyimino-acetyl-amino]-3-(3-thienyl)-3-cephem-4-carboxylicacid (tri-fluoroacetate) ##STR87##

In analogy to the procedure of Example I, 383 mg (66% of theory) of thetitle compound are obtained from 700 mg (1.0 mmol) of the compound fromExample 44.

EXAMPLE XII

7β-[2-(2-Amino-4-thiazolyl)-2-syn-methoxyimino-acetyl-amino]-3-(2-methoxymethyl-3-thienyl)-3-cephem-4-carboxylicacid (trifluoroacetate) ##STR88##

In analogy to the procedure of Example I, 30 mg (28% of theory) of thetitle compound are obtained from 125 mg (0.17 mmol) of the compound fromExample 45.

EXAMPLE XIII

7β-[2-(2-Amino-4-thiazolyl)-2-syn-hydroxyimino-acetylamino]-3-(2-thienyl)-3-cephem-4-carboxylicacid ##STR89##

1.1 g (1.0 mmol) of the compound from Example 46 are stirred at roomtemperature for 1 h with 20 ml of 90% strength formic acid. 1 ml ofconcentrated hydrochloric acid is then added and the mixture is stirredat room temperature for a further 2 h. It is evaporated to dryness invacuo and the residue is chromatographed on HP-20 usingwater/acetonitrile.

Yield: 126 mg (28% of theory)

¹ H-NMR (DCOOD): δ=3.90 (s, 2H, 2--H); 5.41 (d, J=5 Hz, 1H, 6--H); 6.08(d, J=5 Hz, 1H, 7--H); 7.10 (dd, J=5 Hz, J=5 Hz, 1H, 3'--H ); 7.20 (d,J=5 Hz, 1H, 3'--H); 7.39 (s, 1H, 7'-aryl--H); 7.54 (d, J=5 Hz, 1H,3'--H).

The following are prepared in analogy to the procedure of Example XIII:

    ______________________________________                                         ##STR90##                                                                    Example No.: R.sub.1                                                          ______________________________________                                        XIV                                                                                         ##STR91##                                                       XV                                                                                          ##STR92##                                                       XVI                                                                                         ##STR93##                                                       XVII                                                                                        ##STR94##                                                       XVIII                                                                                       ##STR95##                                                       XIX                                                                                         ##STR96##                                                       XX                                                                                          ##STR97##                                                       XXI                                                                                         ##STR98##                                                       XXII                                                                                        ##STR99##                                                       XXIII                                                                                       ##STR100##                                                      XXIV                                                                                        ##STR101##                                                      ______________________________________                                    

EXAMPLE XXV

7β-[2-(2-Amino-4-thiazolyl)-2-syn-hydroxyimino-acetyl-amino]-3-(2-thienyl)-3-cephem-4-carboxylicacid ##STR102##

In analogy to the procedure of Example XXIII, 572 mg (89% of theory) ofthe title compound are obtained from 1.50 g (1.42 mmol) of the compoundfrom Example 16.

EXAMPLE XXVI

7β-[2-(2-Amino-4-thiazolyl)-2-syn-hydroxyimino-acetyl-amino]-3-(2-methoxymethyl-3-thienyl)-3-cephem-4-carboxylicacid ##STR103##

In analogy to the procedure of Example XIII, 28 mg (7% of theory) of thetitle compound are obtained from 700 mg (0.64 mmol) of the compound fromExample 59.

EXAMPLE XXVII

7β-[2-(2-Amino-4-thiazolyl)-2-syn-hydroxyimino-acetyl-amino]-3-(4-bromo-2-methoxymethyl-3-thienyl)-3-cepham-4-carboxylic acid ##STR104##

In analogy to the procedure of Example XIII, 580 rag (91% of theory) ofthe title compound are obtained from 1.10 g (0.93 mmol) of the compoundfrom Example 60.

EXAMPLE XXVIII

7β-[2-(2-Amino-4-thiazolyl)-Z-2-butenoylamino]-3-(3-thienyl)-3-cephem-4-carboxylic acid (sodiumsalt) ##STR105##

¹ H--NMR (DCOOD): δ=2.10 (d, J=7 Hz, 3H, CH₃); 3.83 and 3.91 (2d, J=18Hz, each 1H, 2--H); 5.40 (d, J=6 Hz, 1H, 6--H); 6.04 (d, J=6 Hz, 1H,7--H); 6.60 (q, J=7 Hz, 1H, 7'--CH); 6.86 (s, 1H, 7'--aryl--H); 7.14 (m,1H, 3'--H); 7.48 (m, 2H, 3'--H).

We claim:
 1. A compound of the formula ##STR106## in which X representsa nitrogen atom or the --CH group,Y represents a group of the formulaN--OR₃ or CHR₄, in whichR₃ denotes hydrogen, straight-chain or branchedalkenyl, alkinyl or alkyl in each case having up to 8 carbon atoms,where the latter can optionally be substituted by halogen or byprotected or unprotected carboxyl or amino, R₄ denotes hydrogen, arylhaving 6 to 10 carbon atoms, protected or unprotected carboxyl, halogenor straight-chain or branched alkoxycarbonyl, alkoxy, alkenyl or alkylin each case having up to 8 carbon atoms, where the latter can besubstituted by halogen, hydroxyl, nitro, cyano, carboxyl or bystraight-chain or branched alkoxy or alkoxycarbonyl in each case havingup to 6 carbon atoms, R₁ represents thienyl or furyl which is optionallymonosubstitutecd to trisubstituted by identical or different halogen,trifluoromethyl, trifluoromethoxy or hydroxy substituents or by a groupof the formula --NR₄ R₆ in whichR₅ and R₆ are identical or different anddenote hydrogen, straight-chain or branched alkyl having up to 8 carbonatoms or phenyl, or are substituted by straight-chain or branched alkoxyor alkyl in each case having up to 8 carbon atoms, where the latter canbe substituted by hydroxy, halogen or by straight-chain or branchedalkoxy having up to 6 carbon atoms,R₂ represents hydrogen, or representsa carboxyl protecting group or represents an ester radical which can becleaved in vivo, or a pharmaceutically tolerable salt thereof.
 2. Acompound or salt thereof according to claim 1, in which R₂ represents##STR107## in which R₇ and R₈ are identical or different and denotehydrogen, phenyl or straight-chain or branched alkyl having up to 4carbon atoms,R₉, R_(9'), R₁₀ and R_(10') are identical or different anddenote hydrogen or straight-chain or branched alkyl having up to 4carbon atoms, R₁₁ denotes straight-chain or branched alkyl having up to6 carbon atoms, R₁₂ denotes straight-chain or branched alkyl having upto 6 carbon atoms or cyclohexyl.
 3. A compound or salt thereof accordingto claim 1, in whichX represents a nitrogen atom or the --CH group, Yrepresents a group of the formula N--OR₃ or CH--R₄, in whichR₃ denoteshydrogen or straight-chain or branched alkyl having up to 6 carbonatoms, which is optionally substituted by fluorine, chlorine, bromine orprotected or unprotected carboxyl or amino, R₄ denotes hydrogen, phenyl,carboxyl, fluorine, chlorine, bromine or straight-chain or branchedalkoxy, alkoxycarbonyl or alkyl in each case having up to 6 carbonatoms, where the latter can be substituted by fluorine, chlorine,bromine, hydroxyl, carboxyl or by straight-chain or branched alkoxy oralkoxycarbonyl in each case having up to 4 carbon atoms, R₁ representsthienyl or furyl which is optionally monosubstituted or disubstutited byidentical or different fluorine, chlorine or bromine substituents, or bya group of the formula --NR₅ R₆, in whichR₅ and R₆ are identical ordifferent and denote hydrogen or straight-chain or branched alkyl havingup to 6 carbon atoms, or are substituted by straight-chain or branchedalkoxy or alkyl in each case having up to 6 carbon atoms, where thelatter can be substituted by hydroxyl, fluorine, chlorine or bystraight-chain or branched alkoxy having up to 4 carbon atoms, R₂represents hydrogen, or represents methyl, ethyl, tert-butyl,2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl,triphenylmethyl, acetoxymethyl, allyl, benzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 1-phenoxyethyl, 2-methyl-2-propenyl, 4-nitrobenzyl,2-nitrobenzyl, trimethylsilylethyl or tert-butyl-dimethylsilylethyl, orrepresents a radical of the formula ##STR108##
 4. A compound or saltthereof according to claim 1, in whichX represents a nitrogen atom orthe --CH group, Y represents a group of the formula N--OR₃ or --CHR₄, inwhichR₃ denotes hydrogen or straight-chain or branched alkyl having upto 4 carbon atoms, which is optionally substituted by fluorine, chlorineor by protected or unprotected carboxyl or amino, R₄ denotes hydrogen orstraight-chain or branched alkoxy or alkyl in each case having up to 4carbon atoms, where the latter can be substituted by hydroxyl, carboxyl,methoxy, ethoxy or propoxy, R₁ represents thienyl or furyl which isoptionally monosubstituted or disubstituted by identical or differentfluorine, chlorine, bromine or amino substituents or by straight-chainor branched alkoxy, alkoxycarbonyl or alkyl in each case having up to 4carbon atoms, where the latter can be substituted by hydroxy, fluorine,chlorine, methoxy or ethoxy, R₂ represents hydrogen, or represents aradical of the formula ##STR109##
 5. A compound of salt thereofaccording to claim 1, in whichR₁ represents thienyl or furyl which isoptionally monosubstituted to trisubstituted by identical or differenthalogen, trifluoromethyl, trifluoromethoxy or hydroxyl substituents orby a group of the formula --NR₅ R₆.
 6. A compound or salt thereofaccording to claim 1, in whichR₁ represents a member selected from thegroup consisting of furyl, thienyl, methoxymethylthienyl,methoxymethyl-bromo-thienyl.
 7. A compound or salt thereof according toclaim 6, in whichX represents the --CH group, and Y represents ═N--OH,═N--OCH₃ or ═CH--CH₃.
 8. An antibacterial composition comprising anantibacterially effective amount of a compound or salt according toclaim 1 and a pharmaceutically tolerable diluent.
 9. A method ofcombating bacterial infection in a patient in need thereof whichcomprises administering to such patient an antibacterially effectiveamount of a compound or salt according to claim 1.